The formation of N-nitrosodimethylamine (NDMA) in ranitidine hydrochloride drug substance (DS) and drug products has attracted considerable attention over the last few years. The drug structure is ...unusual in that it contains a vinyl nitro moiety. Although a variety of studies have been carried out to understand how NDMA is formed in the DS solids, a mechanistic description of NDMA formation has remained elusive. A new mechanistic view of NDMA formation is detailed here. Autoxidation of ranitidine can rationalize nitrite ion and dimethylamine liberation from ranitidine. The subsequent nitrosation is argued to be due to conversion of nitrite ion to the gas phase nitrosating agent nitrosyl chloride, NOCl. Oxygen scavenging packaging systems should be able to stop the autoxidation, and thus shut down the nitrite release from ranitidine. Without nitrite release NDMA cannot form. This may provide a practical means to stabilize ranitidine DS and solid dosage formulations against NDMA formation.
Amorphous solid dispersions (ASDs) have been increasingly used to maximize human exposures from poorly soluble drug candidates. One well-studied advantage of ASDs is the increased amorphous drug ...solubility compared to crystalline forms. This provides more rapid dissolution rates. An additional advantage of ASDs is that the dissolution process of the ASD particle may also rapidly transform much of the drug present in the ASD particle to small (<1 μm) amorphous drug nanoparticles which will have fast dissolution rates. This work examines the mechanism by which this nanoparticle formation occurs by studying an ASD consisting of 70–80% copovidone, 20% anacetrapib (a low solubility lipophilic drug), and 0–10% TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate, a surfactant). Nanoparticle formation is found to derive from a rapid amorphous drug domain formation within the ASD particle, driven by copovidone dissolution from the particle. The role of surfactant in the ASD particle is to prevent an otherwise rapid, local drug domain aggregation event, which we term “hydrophobic capture”. Surfactant thus allows the amorphous drug domains to escape hydrophobic capture and diffuse to bulk solution, where they are reported as nanoparticles. This view of surfactant and nanoparticle formation is compared to the prevailing view in the literature. The work here clarifies the different roles that surfactant might play in increasing nanoparticle yields and extending the useful drug loading ranges in copovidone-based ASDs.
This edition provides a balanced view of the field of business process change. Paul Harmon offers concepts, methods, cases for all aspects and phases of successful business process improvement. ...Updated and added for this edition is new material on the development of business models and business process architecture development, on integrating decision management models and business rules, on service processes and on dynamic case management, and on integrating various approaches in a broad business process management approach. New to this edition: how to develop business models and business process architecture; how to integrate decision management models and business rules; new material on service processes and on dynamic case management; learn to integrate various approaches in a broad business process management approach; extensive revision and update addresses Business Process Management Systems, and the integration of process redesign and Six Sigma. --
Nitrosamine impurities may form during drug substance manufacturing processes. Here, we focus on nitrosamine impurity level growth in oral drug products during long term stability studies. ...Nitrosamine growth mechanisms in oral dosage forms are typically framed as due to nitrosating agents that can be formed in solutions of nitrous acid with a required pH value of around pH 5 or below. We strive in this work to bring awareness to pharmaceutical scientists that formaldehyde, common in oral dosage form excipients, has previously been shown in solution to catalyze the reaction between secondary amines and nitrite ion to give nitrosamine products. This mechanism operates at pH ∼6 and higher. We attempt to re-frame the solution work as relevant to pharmaceutical solid dosage forms. Recent examples of solid dosage form product recalls are used to demonstrate the formaldehyde catalyzed nitrosation pathway operating in the solid state.
Poorly water soluble drug candidates have been common in developmental pipelines over the last several decades. This has fueled considerable research around understanding how bile salt and model ...micelles can improve drug particle dissolution rates and human drug exposure levels. However, in the pharmaceutical context only a single mechanism of how micelles load solute has been assumed, that being the direct loading mechanism put forth by Cussler and coworkers (Am Inst Chem Eng J. 1976;22(6):1006-1012) 40 years ago. In this model, micelles load at the particle surface and will be loaded to their equilibrium loading values. More recently, Kumar and Gandhi and coworkers (Langmuir. 2003;19:4014-4026) developed a comprehensive theory of micelle solubilization which also features an indirect loading mechanism which they argue should operate in ionic surfactant systems. In this mechanism, micelles cannot directly load at the solute particle surface and thus may not reach equilibrium loading values within the particle diffusion layer. In this work, we endeavor to understand if the indirect micelle loading mechanism represents a plausible description in the pharmaceutical context. The overall data in SLS and FaSSIF systems obtained here, as well as several other previously published datasets, can be described by the indirect micelle loading mechanism. Implications for pharmaceutical development of poorly soluble compounds are discussed.
Purpose
Nine common excipients were examined to determine their ability to cause disproportionation of the HCl salt of a a weakly basic compound. The goal was to determine which excipients were ...problematic and correlate the results to known properties such as surface pH, slurry pH, or molecular structure. Such a correlation enables a general, simple excipient selection process.
Methods
Binary compacts and “pseudo formulations” are studied after stressing at 40°C/75%RH and 40°C/35% RH for up to 28 days. Near-Infrared (NIR) and X-Ray powder diffraction (XRPD) measurements monitored the conversion of the HCl salt to the free base.
Results
The excipients which induced measureable disproportionation were magnesium stearate, sodium croscarmellose, and sodium stearyl fumarate. Magnesium stearate induced the most extensive and rapid disproportionation at 40°C/75%RH and 40°C/35%RH. Samples containing magnesium stearate showed a unique and significant water uptake above 31%RH.
Conclusions
The problematic excipients are best explained by the proton accepting capacity of excipient carboxylate groups which have pK
a
’s higher than the pH
max
of the drug salt. Alternative lubricants and disintegrants are suggested and a simple excipient screening process is proposed. Magnesium stearate was the most deleterious excipient for HCl salts due to the formation of the deliquescent salt magnesium chloride.
The degrees of freedom afforded by nanocomposite materials and additive manufacturing allow for the precise control over the chromatic properties of gradient index (GRIN) optics. The ability to ...engineer nanocomposite optical materials using blends of three or more constituents makes it possible to independently specify the refractive index gradient and the dispersion of optical materials. The refractive index spectra of the primary nanocomposite feedstock are defined relative to one another using various concentrations of monomers and nanofillers. Inkjet deposition is then used to print-compose specific feedstock to form refractive index gradients with precise control over dispersion. Arrays of 4-mm-diameter spherical GRIN lenses were fabricated using different nanomaterial compositions. The ability to positively and negatively control dispersion and to obtain achromatic performance was demonstrated. Control over partial dispersion is also shown.
Business Process Change, 3 rd Edition provides a balanced view of the field of business process change. Bestselling author Paul Harmon offers concepts, methods, cases for all aspects and phases of ...successful business process improvement. Updated and added for this edition is new material on the development of business models and business process architecture development, on integrating decision management models and business rules, on service processes and on dynamic case management, and on integrating various approaches in a broad business process management approach. New to this edition: * How to develop business models and business process architecture * How to integrate decision management models and business rules * New material on service processes and on dynamic case management * Learn to integrate various approaches in a broad business process management approach * Extensive revision and update addresses Business Process Management Systems, and the integration of process redesign and Six Sigma * Learn how all the different process elements fit together in this best first book on business process, now completely updated * Tailor the presented methodology, which is based on best practices, to your organization's specific needs * Understand the human aspects of process redesign * Benefit from all new detailed case studies showing how these methods are implemented
Business Process Change, 3rd Edition provides a balanced view of the field of business process change. Bestselling author Paul Harmon offers concepts, methods, cases for all aspects and phases of ...successful business process improvement. Updated and added for this edition is new material on the development of business models and business process architecture development, on integrating decision management models and business rules, on service processes and on dynamic case management, and on integrating various approaches in a broad business process management approach.New to this edition: How to develop business models and business process architecture How to integrate decision management models and business rulesNew material on service processes and on dynamic case managementLearn to integrate various approaches in a broad business process management approachExtensive revision and update addresses Business Process Management Systems, and the integration of process redesign and Six SigmaLearn how all the different process elements fit together in this best first book on business process, now completely updated Tailor the presented methodology, which is based on best practices, to your organization’s specific needs Understand the human aspects of process redesignBenefit from all new detailed case studies showing how these methods are implemented
Evaluation of Hydroperoxides in Common Pharmaceutical Excipients Wasylaschuk, Walter R.; Harmon, Paul A.; Wagner, Gabriella ...
Journal of pharmaceutical sciences,
January 2007, 2007-01, 2007, 2007-Jan, 2007-01-00, 20070101, Letnik:
96, Številka:
1
Journal Article
Recenzirano
While the physical properties of pharmaceutical excipients have been well characterized, impurities that may influence the chemical stability of formulated drug product have not been well studied. In ...this work, the hydroperoxide (HPO) impurity levels of common pharmaceutical excipients are measured and presented for both soluble and insoluble excipients. Povidone, polysorbate 80 (PS80), polyethylene glycol (PEG) 400, and hydroxypropyl cellulose (HPC) were found to contain substantial concentrations of HPOs with significant lot-to-lot and manufacturer-to-manufacturer variation. Much lower HPO levels were found in the common fillers, like microcrystalline cellulose and lactose, and in high molecular weight PEG, medium chain glyceride (MCG), and poloxamer. The findings are discussed within the context of HPO-mediated oxidation and formulating drug substance sensitive to oxidation. Of the four excipients with substantial HPO levels, povidone, PEG 400, and HPC contain a mixture of hydrogen peroxide and organic HPOs while PS80 contains predominantly organic HPOs. The implications of these findings are discussed with respect to the known manufacturing processes and chemistry of HPO reactivity and degradation kinetics. Defining critical HPO limits for excipients should be driven by the chemistry of a specific drug substance or product and can only be defined within this context.
